Characterization of eIF3h as a driver of triple negative breast cancer progression

Background: Triple-negative breast cancer (TNBC) has a worse prognosis than other breast cancer subtypes, leading to a 5-year relative survival rate of just 15% if metastasized. TNBC is aggressive and challenging to treat, as it lacks estrogen, progesterone, and HER2 receptors. It also exhibits a high rate of proliferation and chromosome instability and is extremely metastatic. Unfortunately, there are limited effective therapy options for TNBC. In breast and other cancers, tumor cells often alter how they translate genetic signals from mRNA into proteins, allowing them to adapt and become more aggressive. This understudied mechanism is crucial for continuous cell proliferation, survival under physiologic stress, and metastasis. Eukaryotic translation initiation factors (eIFs) are among the master players of protein synthesis and are involved in the formation of large pre-initiation complexes (PICs) containing 40S ribosome subunits and mRNA. PICs, including the eIF3 complex, specifically eIF3h, are involved in mRNA translation and regulate the key processes of translation initiation, including recruitment and disassembly of ribosomes. In metastatic breast tumors, eIF3h is up-regulated, and it forms the basis of cell growth and survival; nevertheless, inhibition decreases cell viability and inhibits colony formation. Nonetheless, its specific function in TNBC metastasis remains relatively unexplored, suggesting that inhibiting eIF3h function may be a potential therapeutic target. Objective/Hypothesis: We hypothesize that increased expression levels of eIF3h are the primary driver of TNBC progression and metastasis, resulting from the activation of oncogenic pathways that promote high-grade TNBC growth, leading to poor overall, relapse-free, and metastasis-free survival. Results: Unpublished preliminary data support this hypothesis. First, survival analyses performed on several large public datasets (GEO, EGA, TCGA) show that high eIF3h expression correlates with reduced overall survival (p = 0.0038), distant metastasis-free survival (p = 0.018), and relapse-free survival (p = 0.0012). Second, transcriptomic data from normal, tumor, and metastatic breast tissues (GDC, GTEx, GEO) revealed significantly increased eIF3h expression in both tumors and metastases (p < 0.0001). Third, genomic profiling conducted using cBioPortal (TCGA) identifies repeated co-alterations in eIF3h-high tumors that modulate the action of anti-apoptotic, autophagic, cell cycle progression, angiogenic, and epithelial-to-mesenchymal transition (EMT) pathways, which mediate tumor progression and metastasis. Conclusions: These findings collectively demonstrate that eIF3h overexpression is a significant negative prognostic risk factor and a contributor to TNBC progression, therapy resistance, and metastasis through the induction of a potent regulatory mechanism for oncogenic translation.